Impact of Metformin on Immuno-virologic Parameters in HIV

A 72 Week, Randomized, Open-label vs Observation Study to Assess the Potential Immuno-virologic Benefit of Metformin in HIV-infected Individuals Receiving Antiretroviral Therapy

Non-diabetic, aviremic HIV-infected individuals on antiretroviral therapy (ART) will be randomized to metformin therapy or to observation for 72 weeks. Primary objective is to assess change over 72 weeks in CD4 T cell negative checkpoint receptors (PD-1 and TIGIT). As secondary objectives the study will look at 72 week change in other immuno-virologic parameters (CD8 T cell negative checkpoint receptors, plasma indoleamine 2,3-dioxygenase (IDO) levels and CD4 T cell and monocyte intracellular HIV DNA and HIV RNA. The study will also explore the 72 week impact of metformin on change in carotid intima-media thickness (cIMT) as a surrogate marker of atherosclerosis, on neuropsychological (NP) performance, strength, and change in body composition.

Study Overview

• Status: Unknown
• Conditions: HIV/AIDS
• Intervention / Treatment: Drug: Metformin

• Study Type: Interventional
• Enrollment (Anticipated): 38
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Debra Ogata-Arakaki, RN; Phone Number: 808 692-1332; Email: ogataara@hawaii.edu
• Study Contact Backup: Name: Cecilia M Shikuma, MD; Phone Number: 808 692-1328; Email: shikuma@hawaii.edu

Study Locations

• United States
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Recruiting
      • John A. Burns School of Medicine, University of Hawaii - Manoa
      • Contact: Debra Ogata-Arakaki, RN; Phone Number: 808 692-1332; Email: ogataara@hawaii.edu
      • Contact: Cecilia Shikuma, MD; Phone Number: 808-692-1328; Email: shikuma@hawaii.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV+
• On suppressive ART stable for > 1 year
• Plasma HIV RNA < 50 copies/mL within 3 months of entry, with no HIV RNA > 200 copies/mL within the past 6 months prior to entry
• Age >40 years
• Ability and willingness to provide written informed consent

Exclusion Criteria:

• Uncontrolled chronic medical condition or cancer
• Acute illness within 2 weeks of entry
• Diagnosis of diabetes by history, fasting blood glucose >126, or by HgbA1c > 6.5
• Chronic, uncontrolled diarrhea
• Known hypersensitivity or contraindication to metformin use
• Current presence of hepatitis C including currently on or intent to start therapy for hepatitis C within the 48 week duration of study.
• Serum B12 level below the reference normal range as listed by the commercial lab utilized for this study (Diagnostic Laboratory Services)
• Pregnancy, or intent to become pregnant or nursing an infant
• Any immunomodulator, HIV vaccine, any other vaccine, or investigational therapy within 30 days of study entry.
• Current uncontrolled coronary artery disease or NYHA Class 3 or 4 congestive heart failure
• History of liver cirrhosis
• Current use of zidovudine, stavudine or didanosine

• The following lab values

  • Hemoglobin < 9.0 g/dL
  • Absolute neutrophil count < 1000/μL
  • Platelet count < 50,000/μL
  • AST (SGOT) and ALT (SGPT) > 5x upper limit of normal (ULN)
  • Calculated creatinine clearance (Cockcroft and Gault) < 50 ml/min
• Active or recent past history (within past 2 years) of illicit substance or alcohol use or abuse which, in the judgment of the Investigator, will interfere with the patient's ability to comply with the protocol requirements
• Patients, who, in the opinion of the Investigator, are unable to comply with the dosing schedule and protocol evaluation or for whom the study may not be advisable

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.	Drug: Metformin; Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.
No Intervention: Observation; Observed without metformin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD4 T cell PD1+TIGIT+	Comparison of change over time in percentage of CD4 T cells bearing the PD1+TIGIT+ surface markers in peripheral blood mononuclear cells (PBMC) in the treatment (metformin) arm compared to the observation arm	Entry to week 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD8 T cell PD1+TIGIT+	Comparison of change over time in percentage of CD8 T cells bearing the PD1+TIGIT+ surface markers in PBMCs in the 2 study arms	Entry to week 72
Plasma levels of indoleamine 2,3-dioxygenase (IDO)	Comparison of change over time in the levels of IDO [assessed as a ratio of L-kynurenine (kyn) to substrate tryptophan (trp)] in mass spectrometry assays	Entry to week 72
Peripheral blood CD4 T cell intracellular HIV DNA	Comparison of change over time in the number of intracellular HIV DNA copies per million CD4 T cells in PBMC in the 2 study arms	Entry to week 72
Peripheral blood CD4 T cell intracellular HIV RNA	Comparison of change over time in the number of intracellular HIV RNA copies per million CD4 T cells in PBMC in the 2 study arms	Entry to week 72
Peripheral blood monocyte intracellular HIV DNA	Comparison of change over time in the number of intracellular HIV DNA copies per million monocytes in PBMC in the 2 study arms	Entry to week 72
Peripheral blood monocyte intracellular HIV RNA	Comparison of change over time in the number of intracellular HIV RNA copies per million monocytes in PBMC in the 2 study arms	Entry to week 72

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability: # of grade 2 or greater adverse events in each arm	Comparison of the # of grade 2 or greater adverse events in the 2 arms	Entry to week 72
Carotid intima-media thickness	Comparison of change over time in the thickness of the right carotid intima-media thickness (mm) as assessed by carotid ultrasound in the 2 study arms	Entry to week 72
Neuropsychological testing global Z score	Comparison of change over time in the age, gender and education-adjusted neuropsychological testing global Z score in the 2 study arms [The z score has a mean of zero and a standard deviation of 1; higher than 0 is better cognitive performance and lower than 0 is lower performance than the mean]	Entry to week 72
Beck's Depression Index II score	Comparison of change over time in the Beck's Depression Index II score in the 2 study arms [21-item rating scale with maximum score of 63; higher scores are indicative of worse depression]	Entry to week 72
Handgrip	Comparison of change over time in handgrip strength (kg) as assessed by a handgrip dynamometer in the 2 study arms	Entry to week 72
Total lean tissue by dual energy absorptiometry (DXA)	Comparison of change over time in total lean tissue (kg) as assessed by DXA in the 2 study arms	Entry to week 72

Collaborators and Investigators

• Sponsor: University of Hawaii
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Cecilia M Shikuma, MD, University of Hawaii

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2019
• Primary Completion (Anticipated): February 1, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: July 31, 2020
• First Submitted That Met QC Criteria: August 4, 2020
• First Posted (Actual): August 5, 2020

Study Record Updates

• Last Update Posted (Actual): August 5, 2020
• Last Update Submitted That Met QC Criteria: August 4, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: H046

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Dataset will be available to other researchers upon request once the primary manuscript is written
• IPD Sharing Time Frame: After the study analyses are completed and primary manuscript is published, and for a duration of at least 5 years afterwards
• IPD Sharing Access Criteria: De-identified dataset will be provided upon request to legitimate researchers
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No